(Taken directly from the application) The endochondral developmental program is four dimensional, one in which spatial relationships among its cells change over time. This proposal focuses on understanding the roles the PTHrP and IHH systems and their secondary mediators play in this complex process, both individually and through effects each system has on the other. Both PTHrP and IHH have strong, but distinguishable influences on this process. Also, there is evidence that PTHrP may mediate some but not all of the actions of IHH, and that the two systems are participants in a feedback system within the developing bone. Our approach takes advantage of genetically-altered mice models: mice null for genes encoding PTHrP, its receptor, or IHH. It also features study of murine hindlimb explants in vitro, where chondrocytic development faithfully mimics in vivo events, and use of carrier beads embedded in explants to deliver local gradients of factors.
Aim I determines the molecules involved in mediating IHH's actions and the interrelationships among these mediators.
Aim II tests the hypothesis that PTHrP antagonizes IHH signaling in IHH-target cells.
Aim III characterizes the roles PTHrP plays in cartilage biology in addition to its role in delaying differentiation, i.e. stimulation of chondrocyte proliferation and actions as a competence factor. These fundamental inquiries into endochondral bone biology have important implications for human disease: deficiencies in genes from the hedgehog signaling pathway have been implicated in such varied conditions as nevoid basal cell carcinoma syndrome and Greig cephalopolysyndactyly syndrome, Jansen's metaphyseal dysplasia is the consequence of a constitutively-active PTH/PTHrP receptor. Furthermore, IHH is the only hedgehog family member whose expression is found postnatally in the skeleton, and the IHH and PTHrP systems as well as their putative secondary mediators have also been shown to be active in fracture repair in adults. Increasing understanding of fundamental issues regarding cartilage biology will yield insight for more rational approaches for treating children with short stature and potentially for treating bone loss diseases, such as osteoporosis.
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